1. Field of the Invention
The present invention relates to a composition for treating and preventing obesity, a composition for suppressing appetite, or a composition for lowering blood sugar, including high water-soluble β-cyclodextrin derivatives, especially, 2-hydroxypropyl-β-cyclodextrin as an effective component.
2. Description of the Related Art
Obesity is one of the most common nutrition disorders around the world and refers to the accumulation of extra calorie in a form of fat in the body through intaking excessive calorie as compared with calorie to be burnt. According to WHO statistical data, the number of overweight people is now approximately 250 million and it is expected to be approximately 300 million who are suffered from obesity after 20 years. Approximately 50% of American adults are suffered from obesity or overweight, i.e., BMI≧25, and it is reported that one of four adults has above 25 of BMI, which means obese, according to the recent domestic statistical data (Ministry of Health and Welfare., Report on 1998 National health and nutrition survey, 2000; Lee B G., et al., J. Kor. Soc. Study Obesity, 11(2), pp 131-140, 2002).
It is generally understood that obesity is caused by various causes, such as a hereditary effect, environmental influences caused by a westernized dietary life, a psychological effect caused by stress, etc., but the accurate cause or mechanism is not precisely established so far. However, there is a lot of interest in an obesity treatment around the world because obesity can cause other diseases, such as cardiovascular disease or diabetes as well as the problems of obesity itself (Manson, et al., New England J. Med., 333, pp 677-685, 1995; Kopleman P G., Nature, 404, pp 635-643, 2000; Must, et al., JAMA, 282, pp 1523-1529, 1999).
In addition, obesity is strongly related to the causes for all sorts of adult diseases, as well as an external problem so that higher the degree of obesity is increased, higher the prevalence rates of diabetes, cholelithiasis, hypertension, a cardiac disorder, a stroke, etc., are increased (Field A E., et al., Arch. Intern, Med., 161(13), pp 1581-1586, 2001; Cha B R., et al., Kor. J. Nutr., 36(5), pp 483-490, 2003). Accordingly, the financial burden and a loss of lives caused by obesity are enormous. The results of the epidemiological survey that was performed in America suggest that the death from the disease related to obesity reached 28,000 in 1991; approximately 80% of them had morbid obesity, i.e., BMI≧30; and approximately 120 trillion won were spent for treating the obesity-related diseases in a year.
It is reported that with the growing interest in the regulation of body weight as mentioned above, 48.1% of women in their 20's and 40% of women in their 30's had the experience in the regulation of body weight during the passing year (Kae S H., Patterns of body weight and diet for Korean-1998 National health and nutrition survey—Proceeding for Korean Community Nutrition., Society spring Conference, 7-28, 2001). Our domestic weight loss market was growing rapidly to be estimated to be 2000 hundred million in 2001 and 3000 hundred million in 2002. It has already been announced that weight-control foods, in which its imports are approved in a normal price, increased by a surprising 110 times in recent 2 years. However, the above products are becoming a problem in the aspect of effectiveness and many examples about side effects in use have been reported (Lee B G., et al., J. Kor. Soc. Study Obesity, 11(2), pp 131-140, 2002; Food and environment, 2002. 9. 18).
Meanwhile, many types of methods and results for treating obesity are presented and living habits have to be reformed basically in order to treat obesity and maintain proper weight because the obesity causes the accumulation of extra energy in the body by intaking excessive energy or reducing energy consumption (Lee B G., et al., J. Kor. Soc. Study Obesity, 11(2), pp 131-140, 2002; Wadden T A., et al., arch. of Intern. Med., 161, pp 218-27, 2001). There are theoretical grounds for preventing the decreases of a basal metabolic rate and fat free mass by intaking calorie with more than basal metabolic rate as a low calorie dietary cure in the process of reforming living habits (Kang J H., et al., J. Kor. Acad. Fam. Med., 19 (2), pp 167-176, 1998).
Meanwhile, another important therapy in addition to a dietary therapy is an exercise cure. It is an established fact that regular exercise is good for the regulation of body weight, but the researches as to whether using a combination of the low calorie dietary cure and regular exercise would be advantageous or not has shown conflicting results according to the researches (Moyer C L., et al., Am. J. clin. Nutr., 50, pp 1324-327, 1989; Donnelly J E., et al., Am. J. clin. Nutr., 54, pp 56-61, 1991).
In addition, a study on body modulating function of various foods is being intensively performed, and also in the field of obesity, the study is proceeding to reduce body weight by using various food materials, such as red ginseng, aloe, hydroxycitrate (HCA), flavonoid, carnitine, chitosan, capsaicin, etc. (Oh S J., et al., J. Kor. Soc. Study Obesity, 9, pp 209-218, 2000; Lee H Y., J. Kor. Soc. Study Obesity, 6, pp 75-84, 1997; Moon S J., et al., Korean J. Nutrition, 30, pp 155-169, 1997).
Despite the developments of the above-mentioned various obesity medicines, there are frequent occasions that fall short of our expectations about the activity of those obesity medicines for suppressing obesity and also induce various side effects, such as dizzy, thirst, vomit, etc., when administering continuously so that there is a still requirement for an effective treatment of obesity.
Diabetes mellitus (DM) is mostly a complex chronic disorder of carbohydrate, fat, and protein metabolisms generated from a lack of cell insulin receptor or a partially or completely lack of insulin secretion by β cells of a pancreas. In the case of an average man, insulin and glucagon are generated in vivo to reduce or increase blood sugar complementarily so that it can maintain a proper concentration of blood sugar in vivo. Insulin is produced, then stored in β cells, and then secreted into blood when increasing blood sugar. The secreted insulin is bonded to an insulin receptor on the surface of muscle cells or hepatic cells to introduce in cells and then D-glucose is introduced from blood into the body to operate a sugar metabolism process.
Only approximately 0.5% of the entire population suffered from diabetes before 1970 in our country so that the medical community had little interest about diabetes, but the rate of patients suffered from diabetes has been estimated to be 2%˜3% in 1980 and 4%˜6% (approximately 1.5˜2 million people) in 1990, and also there are significant numbers of people who did not recognize the fact that they had diabetes.
A symptom of diabetes is very diverse, but polyuria, polydipsia, polyphagia, etc are the most dominant. A patient suffered from diabetes does not use glucose as an energy source so that protein and fat that are already stored are consumed and then a vicious cycle of such phenomenon leads to weight lose.
Diabetes is largely divided into an insulin-dependent diabetes (Type I diabetes) and an insulin-independent diabetes (Type II diabetes). Type I diabetes is in a state of merely secreting insulin through a decrease of pancreatic β cell function due to a genetic cause, a viral infection, etc. Type I diabetes is mainly developed in 10's˜20's by sudden and is known as a juvenile-onset, a brittle, or a ketosis diabetes. The causes of Type II diabetes are unknown, but are well occurred after 40's due to a family history of diabetes, obesity, stress, etc. It is known that for Type II diabetes, insulin is sufficiently secreted in a pancreas but an insulin resistance and glucose uptake are different from the normal so that even though it is hyperinsulinemia, blood sugar does not be normal and there is maturity-onset diabetes, adult-onset diabetes, ketosis-resistant diabetes, or stability diabetes.
Diabetes itself is not a serious disease, but when its treatment is delayed to be chronic, complications, for example diabetic retinopathy (causes of visual impairment, blindness, retinal hemorrhage, retinopathy, and cataracts), diabetic nephropathy, Diabetic Peripheral Neuropathy, cardiac and the circulating system disorders (cause of angiopathy), periodontitis, osteopenia, skin diseases, etc, are problems. The pathologic complications of the diabetes are known to be basically proportional to hyperglycemia (Porte, Jr. et. al., 1996).
Recently, the most commonly used medicine for treating diabetes is largely divided into oral hypoglycemic agents and insulin injections. Generally, it has been the commonly accepted view that insulin should be injected to a patient with insulin-dependent diabetes who cannot secrete insulin in vivo and a patient with insulin-independent diabetes who suffers from gestational diabetes and cannot control blood sugar by using oral hypoglycemic agents, and the oral hypoglycemic agents should be taken by a patient suffered from insulin-independent diabetes who cannot properly control blood sugar even though the patient is combining both exercise and diet.
The insulin injections are intravenously or intramuscular administered, but mostly subcutaneously administrated in the case of a long period of administration. However, in the case of a subcutaneously injection, there is a problem that an insulin effect is decreased because insulin is not sharply increased, when taking in foods, a secretion of insulin is decreased, and it is a liver circulation rather than a peripheral circulation (Goodman, et. al., The Pharmacological basis of Therapeutics, p 1692).
The oral hypoglycemic agents that are generally used may be classified into a sulfonylurea-based drug, a biguanide-based drug, α-glucosidase inhibitor, etc (Deruiter, Endocrine Pharmacology Module, Spring, 2003). Example of the sulfonylurea-based drug includes glipizide, glyclazide, gliquidone, glibenclamide, chlorpropamide, etc, and acts as an accelerator of insulin secretion in a pancreas. Accordingly, they cannot be used for a patient with insulin-dependent diabetes who can never secrete insulin in a pancreas, but they can be used for a patient with insulin-independent diabetes who has a relatively reduced ability for secreting insulin in a pancreas but there is a disadvantage that women of childbearing age cannot use because it can lead to fetal deformities (fetal macrosomia), miscarrige, a stillbirth, etc. In addition, when overdoses of the drugs are administered or administered on an empty stomach, these drugs may cause hypoglycemia and also cause side effects, such as skin rashes, jaundice, loss of appetite, nausea (queasiness), diarrhea, etc. The biguanide-based drug is metformin, etc, has a lower hypoglycemic effect than that of the sulformylurea-based drug, but has low possibility for causing hypoglycemia. However, it is now in use only for an experimental drug in the United States because the side effect rate in a digestive system is high so that nausea, queasiness, diarrhea, rashes, etc are caused at the very beginning of treatment and lactic acidosis is induced to cause a fatal side effect and then threaten one's life.
As mentioned above, a recent method for controlling diabetes is limited only to a few methods and their approaches are different from a natural glycometabolism control of the human body so that it affects negatively the human body thereby requiring the development of the drug for substituting existing insulin and oral hypoglycemic agent.
Cyclodextrin is a ring-shaped oligosaccharide with 6˜12 glucose molecules bonded together in an α-1,4-glycoside bond, and includes alpha(α)-cyclodextrin having 6 glucose molecules bonded, beta (β)-cyclodextrin having 7 glucose molecules bonded, gamma(γ)-cyclodextrin having 8 glucose molecules bonded, delta(δ)-cyclodextrin having 9 glucose molecules bonded, epsilon(ε)-cyclodextrin having 10 glucose molecules bonded, and zeta(ζ)cyclodextrin having 11 glucose molecules bonded. Above this, cyclodextrins having at least 12 glucose molecules are being developed.
The cyclodesxtrin has a three dimensional structure consisting of a hydrophobic inside and a hydrophillic outside so that it is soluble in water and also has a function for including various fat-soluble materials. The above-mentioned function of cyclodextrin can increase solubility of non-soluble materials and also the cyclodextrin can facilitate coverings of taste and smell, stabilization of a deliquescent substance, a decrease of stimulus, etc so that it is being used for a medical industry, a food industry, etc, variously.
Until now, the cyclodextrin may be used for a long life preservation and powderization of toxic volatility, an odorless of bad smell substance, a prevention of flavoring volatilization, a preservation of a flavoring, and a substrate of a powder flavoring; as a drug delivery system including insulin because it includes an effective component of drug, a flavoring and a smell inside of pores, and releases slowly; as a retardative agent or an accelerator of inclusion reaction because it can mix with a unstable material by an inclusion and react with other materials in a state of protecting a part of functional group; as an emulsifier or surfactant because it has an emulsifying function to a non-soluble material; as a stabilizer to an easily oxidizable material or an UV-unstable compound because it prevents an oxidation or photolysis; for removing toxic substances from domestic waste water because it can include harmful heavy metals; as a stabilizer for a long-life quality as a substance for foods or drinks; for preparing packaging products, a fiber, and agricultural products because it can include antimicrobials; as a gel and thickener; and as alternate products for an oil and dietary fibers (Bun-Sam, Lim, a research paper, Korea Institute of Science and Technology Information (KISTI), a ring-shaped multifunctional material cyclodextrin, 2003).
Meanwhile, α-cyclodextrin is commercially available as a diet supplement for losing weight named with FBCx in the United States. When FBCx (10% of the total amount of fat) is added in high-fat feeds including 40% of soybean oil and the feeds are provided to rat for 6 weeks, the rat's weight is reduced by 7.4% as compared with the group of high-fat feeds without FBCx (Artiss J D., et al., Metab. Clin. Exp., 55, pp 195-202, 2006). For a clinical test about obesity with Type II diabetes for 3 months, while the weights of the patients who taken in only diet containing fat are increased, the weights of the patients who taken in the diet containing fat along with FBCx are not decreased but not increased (Grunberger G., et al., Diabetes Metab. Res. Rev. 23, pp 56-62, 2007).
It is known that the α-cyclodextrin has 57 nm of diameter of inside cavity, but β-cyclodextrin further including one molecule of glucose as compared with the α-cyclodextrine has 78 nm of diameter of inside cavity thereby including larger molecule than the α-cyclodextrin so that the interaction with wider variety of molecules can be expected (Brewster M E and Loftsson T., Adv. DrugDeliv. Rev. 59, pp 645-666, 2007). Study on bonding ability of the α-cyclodextrin with fat indicated that the α-cyclodextrin and fat were bonded in the rate of 1:9 confirmed by measuring a level of emulsion formed by the α-cyclodextrin (Grunberger G., et al., Diabetes Metab. Res. Rev. 23, pp 56-62, 2007).
Meanwhile, the experiment for measuring an antiobesity effect using mouse and human indicated that the β-cyclodextrin acts to suppress a weight increase and reduce weight, respectively (Kim D W., et al., Food Sci. Biotechnol., 17, pp 700-704, 2008, Park B S., J. Korean Soc. Food Sci. Nutr. 33, pp 832-838, 2004). However, it is known that the β-cyclodextrin has a relatively low solubility in water (18.5 mg/ml at 25° C.) so that it is difficult to prepare water-soluble formulation with high concentration.
2-hydroxypropyl-β-cyclodextrin is a derivative produced by a reaction between β-cyclodextrin and propylene oxide; and has a higher water-solubility than that of cyclodextrin and is harmless to humans so that it is frequently used as an alternate product for cyclodextrin in a medical and food industry, etc.
Specifically, as the report about a use of 2-hydroxypropyl-β-cyclodextrin, Korean Publication No. 10-1995-0018059 discloses that it was used as absorption and biological agent for increasing utility rate through a rectum mucous membrane of omeprazole; Korean Patent No. 10-0473716 discloses that hydroxypropyl-β-cyclodextrin was used as skin preparation for external use for treating an atopic dermatitis and psoriasis; Korean Publication No. 10-2009-0084925 discloses that it was used as a drug for treating or preventing a congestive heart failure; Korean Publication No. 10-2009-0010953 discloses that it was used as anesthesia, anti-inflammation or anti-pyrogenic drug; Korean Patent No. 10-0441121 discloses that it was used as a composition for a skin care; and Korean Publication No. 10-2008-0046164 discloses that it was used as a drug for reducing a toxic effect of ionizing radiation.
However, there is no report that hydroxypropyl-β-cyclodextrin has an effect on suppressing appetite and reducing weight and body fat. In addition, there is no report that hydroxypropyl-β-cyclodextrin has a hypoglycemic effect after dinner or can be used for treating diabetes.
Accordingly, the present inventors tried to develop anti-obesity drug that is more efficient. As a result of testing the identified stable derivative of β-cyclodextrin, it was confirmed that high water-soluble β-cyclodextrin derivatives, especially, 2-hydroxypropyl-β-cyclodextrin has effects on suppressing a increase in body weight induced by a high fat diet, suppressing appetite through a decrease of dietary intake, decreasing body fat, preventing and treating obesity by reducing liver weight, and preventing and treating various diseases caused by obesity thereby completing the present invention.
In addition, the present inventors tried to develop a new hypoglycermic drug. Consequently, it was confirmed that high water-soluble β-cyclodextrin derivatives, especially, hydroxypropyl-β-cyclodextrin (HPBCD) has an effect on suppressing a sharp increase of blood sugar induced by intaking glucose and maltose on an empty stomach in a normal mouse (ICR) and it can be very useful as an effective component of a pharmaceutically composition for decreasing blood sugar after dinner so that the present invention was completed.